Mimvey

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the
development and maintenance of the female reproductive system and secondary
sexual characteristics. Although circulating estrogens exist in a dynamic
equilibrium of metabolic interconversions, estradiol is the principal
intracellular human estrogen and is substantially more potent than its
metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult
women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily,
depending on the phase of the menstrual cycle. After menopause, most endogenous
estrogen is produced by conversion of androstenedione, secreted by the adrenal
cortex, to estrone by peripheral tissues. Thus, estrone and the
sulfate-conjugated form, estrone sulfate, are the most abundant circulating
estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in
estrogen-responsive tissues. To date, two estrogen receptors have been
identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of
the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone
(FSH) through a negative feedback mechanism. Estrogens act to reduce the
elevated levels of these hormones seen in postmenopausal women.

Progestin compounds enhance cellular differentiation and
generally oppose the actions of estrogens by decreasing estrogen receptor
levels, increasing local metabolism of estrogens to less active metabolites, or
inducing gene products that blunt cellular responses to estrogen. Progestins exert
their effects in target cells by binding to specific progesterone receptors
that interact with progesterone response elements in target genes. Progesterone
receptors have been identified in the female reproductive tract, breast,
pituitary, hypothalamus, and central nervous system. Progestins produce similar
endometrial changes to those of the naturally occurring hormone progesterone.

Pharmacokinetics

Absorption

Estradiol is well absorbed through the gastrointestinal
tract. Following oral administration of estradiol and norethindrone acetate
tablets, peak plasma estradiol concentrations are reached slowly within 5 to 8 hours.
When given orally, estradiol is extensively metabolized (first-pass effect) to
estrone sulfate, with smaller amounts of other conjugated and unconjugated
estrogens. After oral administration, norethindrone acetate is rapidly absorbed
and transformed to norethindrone. It undergoes first-pass metabolism in the
liver and other enteric organs, and reaches a peak plasma concentration within
0.5 to 1.5 hours after the administration of estradiol and norethindrone
acetate tablets. The oral bioavailability of estradiol and norethindrone
following administration of estradiol and norethindrone acetate 1 mg/0.5 mg
when compared to a combination oral solution is 53% and 100%, respectively.
Administration of estradiol and norethindrone acetate 1 mg/0.5 mg with food did
not modify the bioavailability of estradiol, although increases in AUC0-72 of
19% and decreases in Cmax of 36% for norethindrone were seen.

Following continuous dosing with once-daily
administration of estradiol and norethindrone acetate 1 mg/0.5 mg, serum levels
of estradiol, estrone, and norethindrone reached steady-state within two weeks with
an accumulation of 33 to 47% above levels following single dose administration.
Unadjusted circulating levels of E2, E1, and NET during estradiol and
norethindrone acetate 1 mg/0.5 mg treatment at steady-state (dosing at time 0)
are provided in Figures 1a and 1b.

Distribution

The distribution of exogenous estrogens is similar to
that of endogenous estrogens. Estrogens are widely distributed in the body and
are generally found in higher concentrations in the sex hormone target organs.
Estradiol circulates in the blood bound to sex-hormone-binding globulin (SHBG)
(37%) and to albumin (61%), while only approximately 1 to 2% is unbound.
Norethindrone also binds to a similar extent to SHBG (36%) and to albumin
(61%).

Metabolism

Estradiol

Exogenous estrogens are metabolized in the same manner as
endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of
metabolic interconversions. These transformations take place mainly in the
liver. Estradiol is converted reversibly to estrone, and both can be converted
to estriol, which is the major urinary metabolite. Estrogens also undergo
enterohepatic recirculation via sulfate and glucuronide conjugation in the
liver, biliary secretion of conjugates into the intestine, and hydrolysis in
the intestine followed by reabsorption. In postmenopausal women, a significant
proportion of the circulating estrogens exist as sulfate conjugates, especially
estrone sulfate, which serves as a circulating reservoir for the formation of
more active estrogens.

Norethindrone Acetate

The most important metabolites of norethindrone are
isomers of 5α- dihydro-norethindrone and tetrahydro-norethindrone, which
are excreted mainly in the urine as sulfate or glucuronide conjugates.

Excretion

Estradiol, estrone, and estriol are excreted in the urine
along with glucuronide and sulfate conjugates. The half-life of estradiol
following single dose administration of estradiol and norethindrone acetate 1 mg/0.5
mg is 12 to 14 hours. The terminal half-life of norethindrone is about 8 to11
hours.

Special Populations

No pharmacokinetic studies were conducted in special
populations, including patients with renal or hepatic impairment.

Drug Interactions

Co-administration of estradiol with norethindrone acetate
did not elicit any apparent influence on the pharmacokinetics of norethindrone.
Similarly, no relevant interaction of norethindrone on the pharmacokinetics of
estradiol was found within the NETA dose range investigated in a single dose study.

In vitro and in vivo studies have shown
that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4).
Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug
metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum
perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma
concentrations of estrogens, possibly resulting in a decrease in therapeutic
effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such
as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit
juice may increase plasma concentrations of estrogens and result in side
effects.

Clinical Studies

Effects On Vasomotor Symptoms

In a 12-week randomized clinical trial involving 92
subjects, estradiol and norethindrone acetate 1 mg/0.5 mg was compared to 1 mg
of estradiol and to placebo. The mean number and intensity of hot flushes were
significantly reduced from baseline to week 4 and 12 in both the estradiol and norethindrone
acetate 1 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see
Figure 2).

Figure 2 : Mean Weekly Number of Moderate and Severe
Hot Flushes in a 12-Week Study

In a study conducted in Europe a total of 577
postmenopausal women were randomly assigned to either estradiol and
norethindrone acetate 0.5 mg/0.1 mg, 0.5 mg E2/0.25 mg NETA, or placebo for 24
weeks of treatment. The mean number and severity of hot flushes were
significantly reduced at week 4 and week 12 in the estradiol and norethindrone
acetate 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E2/0.25 mg NETA groups compared
to placebo.

Figure 3: Mean Number of Moderate to Severe Hot Flushes
for Weeks 0 Through 12

No. (%) of subjects with endometrial hyperplasia at the end of the study

36 (14.6%)

1 (0.4%)

1 (0.4%)

2 (0.8%)

Effects On Uterine Bleeding Or Spotting

During the initial months of therapy, irregular bleeding
or spotting occurred with estradiol and norethindrone acetate 1 mg/0.5 mg
treatment. However, bleeding tended to decrease over time, and after 12 months
of treatment with estradiol and norethindrone acetate 1 mg/0.5 mg, about 86% of
women were amenorrheic (see Figure 4).

Figure 4 : Patients Treated with Estradiol and
Norethindrone Acetate 1 mg /0.5 mg with Cumulative Amenorrhea over Time
Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 Intent
to Treat Population, LOCF

Note: The percentage of patients who were amenorrheic
in a given cycle and through cycle 13 is shown. If data were missing, the
bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with estradiol and norethindrone
acetate 0.5 mg/0.1 mg, 88% of women were amenorrheic after 6 months of
treatment (See Figure 5).

Figure 5 : Patients Treated with Estradiol and
Norethindrone Acetate 0.5 mg /0.1 mg with Cumulative Amenorrhea over Time
Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent
to Treat Population, LOCF

Effects On Bone Mineral Density

The results of two randomized, multi-center,
calcium-supplemented (500 to 1000 mg/day), placebocontrolled, 2 year clinical
trials have shown that estradiol and norethindrone acetate 1 mg/0.5 mg and
estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women.
While estradiol and norethindrone acetate 0.5 mg/0.1 mg was not directly
studied in these trials, the US trial showed that addition of NETA to estradiol
enhances the effect on BMD, therefore the BMD changes expected from treatment
with estradiol and norethindrone acetate 0.5 mg/0.1 mg should be at least as
great as observed with estradiol 0.5 mg. A total of 462 postmenopausal women
with intact uteri and baseline BMD values for lumbar spine within 2 standard
deviations of the mean in healthy young women were enrolled. In a US trial, 327
postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean
age of 53 years were randomized to 7 groups (0.25, 0.5 mg, and 1 mg of
estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg
estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg
norethindrone acetate, and placebo.) In a European trial (EU trial), 135
postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean
age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone
acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo.
Approximately 58% and 67% of the randomized subjects in the two clinical
trials, respectively, completed the two clinical trials. BMD was measured using
dual-energy xray absorptiometry (DEXA).

A summary of the results comparing estradiol and
norethindrone acetate 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two
prevention trials is shown in Table 3.

US = United States, EU = European
* While estradiol and norethindrone acetate 0.5 mg/0.1 mg was not directly
studied in these trials, the US trial showed that addition of NETA to estradiol
enhances the effect on BMD, therefore the BMD changes expected from treatment
with estradiol and norethindrone acetate 0.5 mg/0.1 mg should be at least as
great as observed with estradiol 0.5 mg.
†Significantly (p < 0.001) different from placebo
‡Significantly (p < 0.007) different from placebo
§Significantly (p < 0.002) different from placebo

The overall difference in mean percentage change in BMD
at the lumbar spine in the US trial (1000 mg/day calcium) between estradiol and
norethindrone acetate 1 mg/0.5 mg and placebo was 5.9% and between estradiol
0.5 mg and placebo was 4.4%. In the European trial (500 mg/day calcium), the
overall difference in mean percentage change in BMD at the lumbar spine was
6.3%. Estradiol and norethindrone acetate 1 mg/0.5 mg and estradiol 0.5 mg also
increased BMD at the femoral neck and femoral trochanter compared to placebo.
The increase in lumbar spine BMD in the US and European clinical trials for
estradiol and norethindrone acetate 1 mg/0.5 mg and estradiol 0.5 mg is
displayed in Figure 6.

†While estradiol and norethindrone acetate 0.5 mg/0.1 mg
was not directly studied in these trials, the US trial showed that addition of
NETA to estradiol enhances the effect on BMD, therefore the BMDchanges expected
from treatment with estradiol and norethindrone acetate 0.5 mg/0.1 mg should be
at least as great as observed with estradiol 0.5 mg.

Treatment with 0.5 mg estradiol decreased biochemical
markers of bone resorption (urinary pyridinoline, urinary deoxypyridinoline)
and bone formation (bone-specific alkaline phosphatase) compared to placebo.
These decreases occurred by 6 months of treatment after which the levels were maintained
throughout the 24 months.

Women's Health Initiative Studies

The WHI enrolled a total of 27,000 predominantly healthy
postmenopausal women in two sub-studies to assess the risks and benefits of
either the use of oral conjugated estrogens (CE 0.625 mg per day) alone or the
use of oral conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate
(MPA 2.5 mg per day) compared to placebo in the prevention of certain chronic
diseases. The primary endpoint was the incidence of coronary heart disease
(CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death), with
invasive breast cancer as the primary adverse outcome studied. A “global index”
included the earliest occurrence of CHD, invasive breast cancer, stroke,
pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture,
or death due to other cause. The study did not evaluate the effects of CE or
CE/MPA on menopausal symptoms.

The estrogen-plus-progestin sub-study was stopped early.
According to the predefined stopping rule, after an average follow-up of 5.2
years of treatment, the increased risk of breast cancer and cardiovascular
events exceeded the specified benefits included in the “global index.” The
absolute excess risk of events included in the “global index” was 19 per 10,000
women-years (RR 1.15, 95% nCI 1.03-1.28).

For those outcomes included in the WHI “global index,”
that reached statistical significance after 5.6 years of follow-up, the absolute
excess risks per 10,000 women-years in the group treated with CE/MPA were six
more CHD events, seven more strokes, ten more PEs, and eight more invasive
breast cancers, while the absolute risk reductions per 10,000 women-years were
seven fewer colorectal cancers and five fewer hip fractures. (See BOXED
WARNINGS, WARNINGS, andPRECAUTIONS.)

Results of the estrogen-plus-progestin sub-study, which
included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White,
6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 4 below:

TABLE 4 : RELATIVE AND ABSOLUTE RISK SEEN IN THE
ESTROGEN-PLUS-PROGESTIN SUB-STUDY OF WHI AT AN AVERAGE OF 5.6 YEARS*

Event

Relative Risk CE/MPA vs. Placebo (95% nCI†)

CE/MPA
n = 8,506

Placebo
n = 8,102

Absolute Risk per 10,000 Women-Years

CHD events

1.24 (1.00-1.54)

39

33

Non-fatal MI

1.28 (1.00-1.63)

31

25

CHD death

1.10 (0.70-1.75)

8

8

All strokes

1.31 (1.02-1.68)

31

24

Ischemic stroke

1.44 (1.09-1.90)

26

18

Deep vein thrombosis

1.95 (1.43-2.67)

26

13

Pulmonary embolism

2.13 (1.45-3.11)

18

8

Invasive breast cancer‡

1.24 (1.01-1.54)

41

33

Invasive colorectal cancer

0.56 (0.38-0.81)

9

16

Endometrial cancer

0.81 (0.48-1.36)

6

7

Cervical cancer

1.44 (0.47-4.42)

2

1

Hip fracture

0.67 (0.47-0.96)

11

16

Vertebral fractures

0.65 (0.46-0.92)

11

17

Lower arm/wrist fractures

0.71 (0.59-0.85)

44

62

Total fractures

0.76 (0.69-0.83)

152

199

*Results are based on centrally adjudicated data.
Mortality data was not part of the adjudicated data; however, data at 5.2 years
of follow-up showed no difference between the groups in terms of all-cause mortality
(RR 0.98, 95% nCI 0.82-1.18).
†Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
‡Includes metastatic and non-metastatic breast cancer, with the exception of in
situ breast cancer.

The estrogen-alone sub-study was also stopped early
because an increased risk of stroke was observed, and it was deemed that no
further information would be obtained regarding the risks and benefits of
estrogen alone in predetermined primary endpoints. Results of the
estrogen-alone sub-study, which included 10,739 women (average age of 63 years,
range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average
follow-up of 6.8 years are presented in Table 5 below.

TABLE 5 : RELATIVE AND ABSOLUTE RISK SEEN IN THE
ESTROGEN-ALONE SUB-STUDY OF WHI*

Event

Relative Risk CE vs.Placebo (95% nCI* )

CE
n = 5,310

Placebo
n = 5,429

Absolute Risk per 10,000 Women-Years

CHD events† Non-fatal MI† CHD death†

0.95 (0.79-1.16)

53

56

0.91 (0.731.14)

40

43

1.01 (0.711.43)

16

16

Stroke‡

1.39 (1.101.77)

44

32

Deep vein thrombosis†,§

1.47 (1.062.06)

23

15

Pulmonary embolism‡

1.37 (0.90-2.07)

14

10

Invasive breast cancer‡

0.80 (0.621.04)

28

34

Colorectal cancer‡

1.08 (0.751.55)

17

16

Hip fracture‡

0.61 (0.410.91)

11

17

Vertebral fractures‡,§

0.62 (0.420.93)

11

17

Total fractures‡,§

0.70 (0.630.79)

139

195

Death due to other causes‡,¶

1.08 (0.881.32)

53

50

Overall mortality‡,§

1.04 (0.881.22)

81

78

Global Index‡,#

1.01 (0.911.12)

192

190

*Nominal confidence intervals unadjusted for multiple
looks and multiple comparisons.
†Results are based on centrally adjudicated data for an average followup of 7.1
years.
‡Results are based on an average follow-up of 6.8 years.
§Not included in Global Index.
¶All deaths, except from breast or colorectal cancer, definite/probable CHD, PE
or cerebrovascular disease.
#A subset of the events was combined in a “global index,” defined as the
earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary
embolism, colorectal cancer, hip fracture, or death due to other causes.

For those outcomes included in the WHI “global index”
that reached statistical significance, the absolute excess risk per 10,000
women-years in the group treated with estrogen-alone was 12 more strokes, while
the absolute risk reduction per 10,000 women-years was six fewer hip fractures.
The absolute excess risk of events included in the “global index” was a
non-significant two events per 10,000 women-years. There was no difference
between the groups in terms of all-cause mortality. (See BOXED WARNINGS,
WARNINGS, andPRECAUTIONS.)

Final adjudicated results for CHD events from the
estrogen-alone sub-study, after an average follow-up of 7.1 years, reported no
overall difference for primary CHD events (nonfatal MI, silent MI and CHD death)
in women receiving CE alone compared with placebo (see TABLE 5).

Women's Health Initiative Memory Study

The estrogen plus progestin Women's Health Initiative
Memory Study (WHIMS) sub-study of WHI enrolled 4,532 predominantly healthy
postmenopausal women 65 years of age and older (47%, age 65 to 69 years, 35%,
age 70 to 74 years, 18%, 75 years of age and older) to evaluate the effects of
CE 0.625 mg plus MPA 2.5 mg daily on the incidence of probable dementia
(primary outcome) compared with placebo.

After an average follow-up of four years, 40 women in the
estrogen-plus-progestin group (45 per 10,000 women-years) and 21 in the placebo
group (22 per 10,000 women-years) were diagnosed with probable dementia. The
relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI,
1.21-3.48) compared to placebo. It is unknown whether these findings apply to
younger postmenopausal women. (See BOXED WARNINGS Cardiovascular And Other Risks, WARNINGS, Dementia, and PRECAUTIONS, Geriatric
use.)

The estrogen-alone WHIMS, a sub-study of the WHI study,
enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and
older (45%, age 65 to 69 years, 36%, age 70 to 74 years, 19%, 75 years of age
and older) to evaluate the effects of conjugated estrogens (CE 0.625 mg) on the
incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 5.2 years, 28 women in the
estrogen-alone group (37 per 10,000 women-years) and 19 in the placebo group
(25 per 10,000 women-years) were diagnosed with probable dementia. The relative
risk of probable dementia in the estrogen-alone group was 1.49 (95% CI 0.83- 2.66)
compared to placebo.

When data from the two populations were pooled as planned
in the WHIMS protocol, the reported overall relative risk for probable dementia
was 1.76 (95% CI 1.19-2.60). Differences between groups became apparent in the
first year of treatment. It is unknown whether these findings apply to younger postmenopausal
women. (See BOXED WARNINGS, WARNINGS, Dementia, and PRECAUTIONS,
Geriatric use.)

Last reviewed on RxList: 4/1/2014
This monograph has been modified to include the generic and brand name in many instances.